The stomach may be contemplated to be an extension of the oesophagus, which function is to store the food. The food stays in the stomach between 1 and 6 hours. During the stay the food becomes more like a thin paste or gruel, and is leaked in small portions to the duodenum. In order to process the food several enzymes are produced by the epithelial cells. Furthermore, the parietal cells produce hydrochloric acid, also called stomach acid, which is responsible for the low pH in the stomach. Furthermore, the acid is a first line immune response to foreign organisms by having a sterilizing effect on bacteria, fungi and other microorganisms.
Although a life essential component excess stomach acid is a widespread problem which seems to be related to the lifestyle of today. Stress, wrong intake of food leading to obesity, eating or drinking too quickly, and gulping down frizzy drinks can cause discomfort relating to stomach acid.
Dyspepsia, also known as indigestion, is a general term for the pain or discomfort a person can feel in the stomach and under the ribs, usually after eating or drinking e.g. alcoholic beverages or coffee, although similar symptoms can occur on an empty stomach.
Some people experiences indigestion a few times per year whilst others suffer every day with symptoms ranging from mild discomfort lasting a few minutes to longer lasting severe pain, sometimes accompanied by nausea and vomiting, which can go on for several hours.
The most common indigestion symptoms are: pain or discomfort in the stomach and under the ribs, heartburn, feeling of being bloated or uncomfortably full after eating, rumbling or gurgling noises in the stomach, stomach cramps, a clenched or knotted feeling in the stomach, excessive burping or flatulence, trapped wind, and nausea or vomiting.
The disorder is experienced by an increasing number of people in the developed world. At least one third of the population suffers from episodic dyspepsia. Dyspepsia is generally relieved by antacids. Antacids are normally over-the-counter products, which can be purchased at any pharmacy. Calcium carbonate is commonly used as the active ingredient in antacids. Some calcium-based antacids add other ingredients, such as magnesium or aluminium. Common over-the-counter antacids include: Tums, which is simply calcium carbonate; Rennie, which has magnesium added to ease the potential side effect of constipation with too much calcium; and Maalox, which has aluminium added to calcium carbonate and comes as liquid or tablet forms. Antacids are useful as self-medication in dyspeptic patients with mild or moderate heartburn.
The clinical efficacy of antacids is well documented (Häcki W H: Diskrepanz zwischen In-vivo und In-vitro Säurebindungs-kapazitäten von Magaldrat (Riopan), Gelusil und Maaloxan in Häcki W H, Conti F, Uehlinger M (eds): Magaldrat. Experimentelle und klinische Erfahrungen. Nürnberg, Verlag Christian M. Silinsky, 1985, pp 57-61; Hürlimann S, Michel K, Inauen W, Halter F: Effect of Rennie Liquid versus Maalox Liquid on intragastric pH in a doubleblind, randomized, placebo-controlled, triple cross-over study in healthy volunteers. Am J. Gastroenterol. 1996; 91: 1173-1180; Feldman M: Pros and cons of over-the-counter availability of histamine2-receptor antagonists. Arch Intern Med 1993; 153; 2415-2424; Netzer P, Brabetz-Hoefliger A, Bruendler R, Flogerzi B, Huesler J, Halter F: Comparison of the effect of the antacid Rennie versus low dose; and H2-receptor antagonists (ranitidine, famotidine) on intragastric acidity. Aliment Pharmacol Ther 1998; 12: 337-342).
Antacids are fast-acting but also short-acting, so they are less useful for frequent or severe heartburn and do not work well as a preventive measure. Acid blockers for heartburn and acid reflux are generally used for severe and chronic symptoms. These drugs work by blocking how much stomach acid is being produced. These acid blockers are not as fast-acting as antacids, but last longer and can be effective for several hours at a time. Over-the-counter acid blockers include Axid, Pepcid, Tagamet, and Zantac. These brands are also available in prescription strength if the more mild forms do not bring enough relief.
Acid blockers work by blocking a type of histamine produced by the stomach, which in turn blocks acid production. These histamine blockers are typically taken twice a day, 30 to 60 minutes before eating to be most effective. The acid blockers are best used as a preventive measure, rather than for sudden, fast relief of symptoms.
Drugs called proton pump inhibitors, or PPIs, shut down tiny proton pumps in the stomach that produce acid, lowering acid levels dramatically. They are often used when histamine blockers do not provide enough relief or when people have erosions in the oesophagus or other complications from GERD (Gastro Esophageal Reflux Disease). One proton pump inhibitor, Prilosec, is available over the counter in certain countries. Others, such as Aciphex, Nexium, Prevacid, Protonix, and stronger Prilosec may require a doctor's prescription depending on the regional requirements.
Reglan is another prescription drug that works to stop acid reflux by speeding up how quickly the stomach empties. Reglan strengthens the digestive contractions that move food through your oesophagus. Faster digestion means less heartburn.
Gaviscon, an over-the-counter heartburn treatment, works as both an antacid and a foam barrier where the oesophagus empties into the top of the stomach. When the tablet is swallowed or the liquid is inBested, the antacid neutralizes stomach acid and the foaming agent creates a physical barrier that helps prevent acid reflux.
Gaviscon is described in GB-A-1,524,740. The prior art document discloses pharmaceutical compositions for the suppression of gastric reflux comprising a low viscosity grade sodium alginate for which the viscosity of a 1% weight volume aqueous solution, when determined on a Brookfield viscometer model RVT using spindle No. 1 at 20 rpm at 25° C. is from 3 to 60 centipoise, from 0.16 to 2.60 parts by weight of sodium bicarbonate per part by weight of sodium alginate and from 0.10 to 1.04 parts by weight of calcium carbonate per part by weight of sodium alginate. The compositions may be administered orally in the form of a dry powder or aqueous suspension which may also contain a suspending agent and/or a preservative. The preparation reacts with gastric acid to form a raft on the contents of the stomach. A liquid formulation comprises an aqueous medium containing 2.5 to 8.0% weight/volume of the low viscosity grade sodium alginate is disclosed. To suspend the calcium carbonate particles in the aqueous medium a suspending agent like acrylic polymer cross-linked with 1% by weight allyl-sucrose is used.
An improved pourability is obtained in GB 2298365 which relates to a pharmaceutical liquid composition comprising potassium bicarbonate instead of sodium bicarbonate and at least 8% w/v sodium alginate. The composition obtains a viscosity which does not possess thickening problems even when stored at low temperatures. The viscosity of a 10% w/v alginate composition falls within the range 200-1500 mPas. The prior art document describes the use of Protanal LFR 5/60 as the alginate of the composition. Salt of divalent metal ions, such as calcium carbonate, are generally included in the pharmaceutical composition in an amount of 8 to 32 g/100 g alginate in order to obtain a satisfying raft formation.
U.S. Pat. No. 6,395,307 also relates to a method for treating reflux oesophagitis as well as dyspepsia using alginates such as Protanal LFR 5/60. It further relates to the preparation of a pourable liquid sodium alginate composition. The composition preferably comprises alginates with a higher mannuronic acid residue to guluronic acid residue ratio and a sodium alginate content of 8 to 15% w/v. The composition further comprises an amount of bicarbonate. The inventors found that bicarbonate, e.g. sodium bicarbonate, is required in order to produce adequate carbon dioxide in the stomach to obtain a proper raft formation of the alginate.
GB-A-2324725 discloses a pharmaceutical composition suitable for forming a mucoadhesive lining in the gastrointestinal tract. It comprises an alginic acid or alginate salt with an M/G ratio of at least unity. The composition may be formulated as a liquid for treatment of reflux oesophagitis. In the examples 32 g calcium carbonate or 100 g of a 10% aluminium hydroxide gel is used per 100 g sodium alginate for the formation of the raft.
WO 01/87282 relates to the treatment of reflux oesophagitis using alginates to inhibit proteolytic enzymes. Especially the invention relates to inhibiting the proteolytic activity of pepsin and/or gastric juice.
According to the invention, one or more sodium alginates with a preferred molecular weight of less than 400 kD are used. The one or more alginate may comprise Protonal LFR 5/60. The pharmaceutical composition may be in the form of a dry powder, which can be admixed with water. Furthermore, the concentration of the preparations in liquid form preferably contains the amount of from 0.1 to 12% w/v of alginate. The viscosity of the solution for LFR 5/60 is measured to 6 mPas for a 1% solution. The composition further comprises a neutralising agent for neutralising gastric acid such as sodium hydroxide.
The composition preferably also comprises divalent or trivalent metal cations to strengthen the formation of a raft. The cations may be calcium or aluminium ions. According to the examples the composition contains in the amount of from 16 to 60 g of calcium carbonate per 100 g alginate.
Gaviscon and similar products exercise its effect by dissolving the solid calcium carbonate salt in the stomach under the influence of the acid gastric fluid. The increasing calcium concentration will stimulate the alginate gelation as calcium ions and the polysaccharides form a rigid matrix. Furthermore, the dissolving of calcium carbonate and sodium bicarbonate will liberate CO2 gas which will be entrapped in the alginate matrix thereby forming foam.
Apart from the inconvenience of the consumption an inhomogeneous product, Gaviscon and products derived thereof furthermore have the disadvantage that the consumer may not obtain the calcium salt in a proper dose for an optimal gelation to progress. More importantly, the sodium alginate salt will not be available and react with the acid present in the stomach because it is occupied with calcium ions in an “egg box” structure.
US 2007/0281015 describes an antacid pharmaceutical composition for the rapid and prolonged neutralization of gastric acidity with mucosa-protecting activity. The pharmaceutical is intended as a liquid preparation for oral ingestion. It includes at least 30% of sodium alginate, an antacid soluble agent, and an inhibitor of proton pump, such as omeprazol. The antacid soluble agent of choice is sodium bicarbonate, which neutralizes hyperacidity acting directly in the digestive tract, the alginate form a viscous suspension or gel after it has entered the stomach environment exerting protecting activity over gastric mucosa, and the inhibitor of a proton pump acts by selectively blocking the H+/K+-ATPase enzyme of stomach parietal cells.
It is the object of the present invention to bring about anticids containing alginates, which have an instant as well as a longer lasting effect on neutralizing stomach acid.